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Neutrophil-Derived Alpha Defensins Control Inflammation by Inhibiting Macrophage Mrna Translation

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Neutrophil-Derived Alpha Defensins Control Inflammation by Inhibiting Macrophage Mrna Translation Neutrophil-derived alpha defensins control inflammation by inhibiting macrophage mRNA translation Matthew Brooka,1, Gareth H. Tomlinsonb,1, Katherine Milesb,1, Richard W. P. Smitha, Adriano G. Rossib, Pieter S. Hiemstrac, Emily F. A. van ’t Woutc, Jonathan L. E. Deand, Nicola K. Graya, Wuyuan Lue,f, and Mohini Grayb,2 aMedical Research Council (MRC) Centre for Reproductive Health, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, Scotland; bMRC Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, Scotland; cDepartment of Pulmonology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands; dKennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, United Kingdom; eInstitute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201; and fDepartment of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201 Edited by Lionel B. Ivashkiv, Hospital for Special Surgery, New York, NY, and accepted by the Editorial Board February 29, 2016 (received for review February 9, 2016) Neutrophils are the first and most numerous cells to arrive at the within the azurophil granules of neutrophils, of which HNP1 is the site of an inflammatory insult and are among the first to die. We most abundant (6–9). They share a similar triple-stranded β-sheet previously reported that alpha defensins, released from apoptotic structure, which is critically held together by three intramolecular human neutrophils, augmented the antimicrobial capacity of disulphide bridges. Once the azurophil granules fuse with macrophages while also inhibiting the biosynthesis of proinflam- phagosomes, they release high concentrations of α-defensins close matory cytokines. In vivo, alpha defensin administration protected to the pathogen surface, where their amphipathic nature allows mice from inflammation, induced by thioglychollate-induced peri- them to rapidly gain entry to the cell’s membrane (10). The per- tonitis or following infection with Salmonella enterica serovar meabilization of membranes by α-defensins is believed to be crucial Typhimurium. We have now dissected the antiinflammatory mech- for their ability to kill microbes and host cells, elicited by mem- anism of action of the most abundant neutrophil alpha defensin, brane disruption and leakage of cellular contents (9, 11). Impor- Human Neutrophil Peptide 1 (HNP1). Herein we show that HNP1 tantly, however, α-defensins only kill proliferating Escherichia coli enters macrophages and inhibits protein translation without in- and a simple model of “death by pore formation” is inadequate to ducing the unfolded-protein response or affecting mRNA stability. explain all their antibacterial properties (12). They have also been In a cell-free in vitro translation system, HNP1 powerfully inhibited noted to inhibit bulk bacterial protein synthesis in E. coli, although both cap-dependent and cap-independent mRNA translation while this is thought to be a consequence of membrane disruption and is maintaining mRNA polysomal association. This is, to our knowl- temporally associated with cell death (11, 12). Additionally, fol- edge, the first demonstration of a peptide released from one cell lowing HIV-1 infection, α-defensins play a crucial role in inhibiting type (neutrophils) directly regulating mRNA translation in another their life cycle (13, 14), suggesting that they have at their disposal a (macrophages). By preventing protein translation, HNP1 functions number of different mechanisms to kill diverse pathogens (7, 15). as a “molecular brake” on macrophage-driven inflammation, en- suring both pathogen clearance and the resolution of inflamma- Significance tion with minimal bystander tissue damage. macrophages | α-defensins | mRNA translation | inflammation | cytokines Neutrophils are the major effectors of acute inflammation responding to tissue injury or infection. The clearance of apo- ptotic neutrophils by inflammatory macrophages also provides eutrophils, via the release of key inflammatory mediators, a powerful proresolution signal. Apoptotic or necrotic neutro- Nconvey signals to practically all other immune cells, orches- phils also release abundant amounts of the antimicrobial pep- trating both the innate inflammatory and subsequent adaptive tides alpha defensins. In this report, we show that the most immune responses (1). Through the de novo generation of lipid abundant of these peptides, HNP1 (Human Neutrophil Peptide 1), mediators, they are also key players in the resolution of inflammation profoundly inhibits protein translation. It achieves this without (reviewed in ref. 2). Following neutrophil apoptosis, their subsequent affecting mRNA stability or preventing mRNA polysomal associ- uptake by human monocyte-derived macrophages (HMDMs) in- ation. This is, to our knowledge, the first demonstration of a duces complex phenotypic changes, including the release of the im- peptide released from one cell, a leukocyte, entering and di- munosuppressive cytokines IL-10 and TGF-β (reviewedinref.3).We rectly modulating the translatome of another cell. It alludes to previously reported that the human antimicrobial peptides α-defen- a previously unidentified mechanism, driven by dying neu- sins [which are released following apoptosis, necrosis, or NET-osis trophils, that ensures the timely resolution of macrophage- (4) of neutrophils] also inhibited the secretion of multiple cytokines driven inflammation, without compromising antimicrobial fromactivatedHMDMsforupto72h,withfullrecoverythereafter function. and no effect on cell viability (5). In vivo, in mice, neutrophil derived α-defensins, given at the time of inducing peritonitis, led to a di- Author contributions: M.B., N.K.G., W.L., and M.G. designed research; M.B., G.H.T., K.M., R.W.P.S., and E.F.A.v.t.W. performed research; A.G.R., P.S.H., J.L.E.D., and W.L. contributed minished inflammatory exudate (5). In addition, mice infected with new reagents/analytic tools; M.B., G.H.T., N.K.G., and M.G. analyzed data; M.B. and M.G. pathogenic Salmonella enterica serovar Typhimurium showed a re- wrote the paper. α duced bacterial load and serum TNF levels upon administration of The authors declare no conflict of interest. α α exogenous -defensin. Hence, neutrophil-derived -defensins were This article is a PNAS Direct Submission. L.B.I. is a guest editor invited by the Editorial able to affect profound changes in the inflammatory environment Board. while also serving as effective antimicrobial peptides. 1M.B., G.H.T., and K.M. contributed equally to this work. – Alpha defensins are small (3 4 kDa) cationic peptides that form 2To whom correspondence should be addressed. Email: [email protected]. part of a larger family of defensins (that also includes beta and This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. theta peptides). Four structurally related peptides (HNP1–4) exist 1073/pnas.1601831113/-/DCSupplemental. 4350–4355 | PNAS | April 19, 2016 | vol. 113 | no. 16 www.pnas.org/cgi/doi/10.1073/pnas.1601831113 Downloaded by guest on September 27, 2021 A BCD 12 Fig. 1. HNP1 inhibits bulk protein synthesis, which 3 IL6 Melle *** 10 is dependent on HNP1 tertiary structure. (A and B) IL1 HNP1-treated HMDMs were stimulated with the 8 HNP1 ** 2 * TLR7 ligand R848 (1 μg/mL) (A)orwith3μg/mL g/ml *** g/ml W26A n **** n 5 CD40L + 5 ng/mL IFNγ (B) for 18 h. TNFα (A) and IL-6 4 **** 1 * LHNP1 β * ** and IL-1 (B) were assayed by ELISA. (C and D) TNF ** TNF HNP1 ** *** R848 HMDMs were stimulated as for A and treated with cytokine g/ml cytokine Melle 0 ** 12.5 μg/mL of HNP1 or the mutant peptides LHNP, 0 400 800 0 5 10 15 0 5 10 20 50 0 5 10 15 W26A, or Melle at the same (C) or variable con- HNP g/ml HNP g/ml TNF g/ml HNP g/ml centrations (D). TNFα assayed by ELISA after 18 h. EFResults are representative of five independent 4hr 18hr experiments. One-way ANOVA with Dunnett’s 1.5 Cellular Secreted Cellular Secreted ** multiple comparison tests; **P < 0.01, *P < 0.05. CD40/IFN --++--++ --++--++ (E) Methionine-starved HMDMs were then cultured ** * with 10 μCi/mL [35S]methionine ± activation (with HNP1 -+-+-+-+ -+-+-+-+ * 1.0 3 μg/mL CD40L and 5 ng/mL IFNγ) and ± addition of HNP1 (25 μg/mL) for 4 or 18 h. Secreted and in- 35S-Met- tracellular proteins were resolved by SDS/PAGE. labelled Phosphorimages of radiolabeled cellular and se- proteins 0.5 creted protein gels show de novo protein synthesis. S-Met incorporation incorporation S-Met (F) De novo protein synthesis of 35S-Methionine– 35 labeled proteins following 18 h of culture, quanti- 0.0 fied by scintillation counting and normalized to un- C/IFN -- + ++- - + treated controls. n = 3. Error bars represent mean ± HNP1 - + - + --+ + SEM; **P < 0.01, *P < 0.05 (Tukey’s post hoc test Cellular Secreted following a one-way ANOVA). In favor of this hypothesis is the observation that α-defensin di- secreted proteins in unstimulated HMDMs and robustly inhibited merization (which requires a tryptophan residue at position 26) is the labeling of secreted proteins in CD40L/IFNγ-stimulated vital for its ability to kill Staphylococcus aureus (16) but has little HMDMs, possibly reflecting the highly secretory phenotype of the effect on its ability to kill E. coli (17). stimulated macrophage. As expected, secreted TNFα was signifi- We wished to understand how α-defensins could simultaneously cantly reduced by HNP1 (Fig. S1A). However,
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